2,3-DIHYDRO-5-ARYL-5H-BENZ{8 f{9 IMIDAZO{8 2,1-a{9 ISOINDOL-5-OLS

ABSTRACT

2,3-DIHYDRO-5-ARYL-5H-benz(f)imidazo(2,1-a)isoindol-5-ols have been prepared which are pharmacologically active as antidepressant.

United States Patent I I I I I Theodore S. Sulkowski Wayne;

Albert A. Mascitti, Norristown, both of Pa. 18,3 1 0 Mar. 10, 1970 Nov. 30, 1971 American Home Products Corporation New York, N.Y.

Inventors Appl. No. Filed Patented Assignee 2,3-DIHYDRO-5-ARYL-5H-BENZ[F]IMIDAZO[ 2,1- AllSOINDOL-S-OLS 6 Claims, No Drawings US. Cl 260/309.6, 260/239.9, 260/294.8 A, 260/295 A, 260/295 T, 260/295 F, 260/296 P, 260/309.7, 260/325,

OTHER REFERENCES Metlesics et al. I J. Org. Chem. Vol. 33, pages 2874 2877 (I968). QD24IJ6 Metlesics et :11. ll Republic of South Africa Patent Journal Vol.2, No. I, pages 90- 9I I969, Jan. I969).

Metlesics et al. III Chem. Abst. Vol. 71, No. 6l,384r I969, Sept. 29; I969) QDLASI Sulkowski et al. J. Org. Chem. Vol. 32, pages 2180- 2I84 (I967). QD24IJ6 Sulkowski I Republic of South Africa Patent Journal Vol. I, No. I0,page l44(l968,0ct. I968).

Sulkowski ll Chem. Abst. Vol. 71, No. 340Ih I969, July 7, I969). QDLASI Primary Examiner-Natalie Trousof AlwrneysAndrew Kafko and Joseph Martin Weigman ABSTRACT: 2,3-dihydro-5-aryI-5H-benz[ flimidazol 2, i a]isoindol-5-ols have been prepared which are pharmacologically active as antidepressant.

2 ,3-Dll-lYDRO-5-ARYL-5 H-BENZ[F]IMIDAZO[ 2, 1 AIISOINDOL-S-OLS DESCRIPTION OF THE INVENTION The new and novel pharmacologically active compounds within the scope of the invention are represented by formula 1:

wherein R is selected from the group consisting of hydrogen,

halogen, amino, (lower)alkylamino, (lower)alkyl and (lower)alkoxy; R, is hydrogen when R, and R are dissimilar and when R, and R, are the same they are both selected from the group consisting of hydrogen, halogen, (lower)alkyl and (lower)alkoxy; R, is selected from the group consisting of phenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alk0xyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyl and tetrahydro-2-naphthyl; R, is selected from the group consisting of hydrogen, (lower)alkyl and gem di(lower)alkyl; and the phannaceutically acceptable salts thereof.

The term (lower)alkyl is used to described hydrocarbon radicals, straight and branched, of from one to about six carbon atoms, illustrative members of the group being methyl,

ethyl, mpropyl, i-propyl, n-butyl, n-hexyl and the like. The terms halogen" and halo" are used to describe the group consisting of fluoro, chloro, bromo and iodo. The term gem is employed herein to signify that a single carbon atom is disubstituted with the particular substituents. See Hackks Chemical Dictionary, 3rd Edition, The Blakiston Company, Phila. (1944 )p. 373.

The compounds of the invention may be prepared by the following reaction scheme:

COOH R4 (III) wherein R, R and R are the same as hereinabove described; the parenthetical (H) of formula III is employed to indicate that hydrogen is not present when R, signifies gem di(lower)alkyl; R, is selected from the group consisting of (lower)alkylsulfonyl, phenylsulfo'nyl, monohalophenylsulfonyl, dihalophenylsulfonyl, mono(lower)alkylphenylsulfonyl,

di(lower)alkylphenylsulfonyl and (lower)alkoxyphenylsulfonyl; X is halogen.

A 3-aroyl-2-naphthoic acid and ethylene diamine or the appropriate ethylene diamine derivative are condensed by refluxing the reactants for from about 2 to about 18 hours. The condensation is preferably carried out in an inert solvent, such as toluene, xylene, benzene, pyridine etc. The reaction mixture is extracted with water and the organic portion is evaporated to dryness. Subsequently the product may be recrystallized from ethanol or ethyl acetate. This intermediate is then sulfonylated with substantially equimolar quantity of an alkyl or aryl sulfonyl halide in pyridine. The reaction is preferably conducted at reflux temperatures for a period of from about 2 to about 18 hours After the above reaction is complete, the sulfonylated product is recovered by customary isolation procedures.

The above prepared sulfonyltetrahydrobenz[f ]imidazoisoindolone may be hydrolyzed and rearranged by admixture with from about to about percent sulfuric acid. The product of the hydrolysis is the sulfate salt of formula Vl which may be recovered by conventional means. Alternatively, the reaction mixture is neutralized by the addition of a base and the resulting precipitate recrystallized from an appropriate organic solvent such as a lower alkanol, dioxan, dimethylformamide and dimethylacetamide to afford an appropriate dihydrobenz[f]imidazoisoindol.

The above procedure may be modified by instead of directly sulfonylating the compound of fonnula IV; the following procedure may be employed:

wherein R, R, R, and R are the same as hereinabove described.

The usual procedure involves heating a compound of formula IV on a steam bath in the presence of about 40 to about 60 percent hydrochloric acid. Therefore the sulfonylation is carried out in the manner set forth above.

The compounds of formula VI may exist in different tautomeric structures and when placed in solution have the following equilibrium:

It is understood that all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

The active compounds of the invention react with acids to form salts. All such nontoxic pharmaceutically acceptable acid addition salts are within the scope of the invention. Suitable acids for the formation of acid addition salts include hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, acetic, lactic, citric, tartaric, maleic, gluconic, benzenesulfonic, toluenesulfonic, methylsulfonic, ethylsulfonic, and the like.

The compounds of formula I are pharmacologically active as antidepressant agents when administered orally to mammals.

The compounds have been orally administered to a group of six mice (three males and three females). One hour later the animals are challenged with reserpine, 2.5 mg./kg. administered intraperitoneally. The degree of ptosis for each eye was determined at l and 2 hours post treatment. Prevention of resperpine ptosis is an indication of antidepressant activity. See Rubin et a1. J.P.E.T. 120, 125 (1957). Controls are simultaneously run with amphetamine and Tofranil. The compounds of formula I were found to be active in mice at a dose of about 0.15 to about 10 mg./kg. of body weight when administered orally.

The compounds have been tested for anorexiant activity according to the following procedure:

Male Charles River rats between 120 and 140 grams are trained to drink sweetened condensed milk from a graduated drinking tube. After a short learning period the animals are placed on a routine of water ad lib for 24 hours, standard laboratory chow for 22 hours and sweetened condensed milk for 2 hours. The volume of milk consumed is measured at 30 minutes as well as 2 hours. The animals are weighed every day. This schedule is maintained days a week over a period of several months. Drug trials are run on Thursdays and changes in milk consumed and 24 hour weight changes are compared to the average of the two days before drug administration.

Animals are tested as groups of six and one group is given saline each week to serve as controls. Drugs are usually administered intraperitoneally in saline or orally in water.

The compounds of the invention did not inhibit appetite when treated at dosage levels of up to mg./kg. of body weight, P0.

In naming the compounds wherein R is other than hydrogen the alternate nomenclature has been employed. This is because the tautomerism of the -NHC N- moiety does not permit any absolute prediction as to the positioning of the (1ower)alkyl or gem di(1ower)alkyl substituent. When the steric influence of the substituent group is considered the probability is great that the product is a 2-(lower)alkyl or 2,2- di(lower)alkyl compound. As the available evidence does not conclusively eliminate the possibility of a 3-(lower)alkyl or a 3,3-di(1ower)alkyl compound, the alternative nomenclature has been employed herein.

The following examples are added to illustrate but not to limit the scope of the invention:

EXAMPLE 1 A solution of 9 g. of 3-(p-chlorobenzoyl)-2-naphthoic acid, 25 ml. of ethylenediamine, and 150 ml. of toluene are refluxed in a flask equipped with a water separator. After refluxing 18 hours, the mixture is extracted with water. The organic portion is evaporated to dryness. The residue is recrystallized from ethanol to obtain 1 lb-(p-chlorophenyl)-1,2,3,l 1btetrahydro-5H-benz[f]imidazo[2,l-alisoindol-S-one, m.p. 2179a% c.

Anal. Calcd for C ,,H, C1N 0: C, 71.75; H, 4.56; N, 8.37;

CI. 10.91. Found: C, 71.76; H, 4.47; N,8.03; Cl. 10.5.

EXAMPLE II In a manner analogous to example I, 3-benzoyl-2-naphthoic acid is reacted with ethylenediamine to obtain l,2,3,l 1b tetrahydro-l 111 -phenyl-5H-benz[f ]imida.zo[2,l-a]2,lalisoindol-S-one, m.p. 2324 C. (Rx EtOH).

Anal. Calcd for C ,,H N 0: C, 79.98; H, 5.37; N, 9.33.

Found: C, 79.91; H,5.31; N, 9.27.

EXAMPLE III In a manner analogous to example I, 3-benzoyl-2--naphthoic acid is reacted with 1,2-diaminopropane to obtain 1,2,3,l lb-tetrahydroZ-methyl-l lb-phenyl- SH-benz [F]imidazo-[2,l-alisoindol-S-one, m.p. 180-5 C. (Rx EtoH).

Anal. Calcd for C H N O: C, 80.23; H5.77; N, 8.91.

Found: C, 80.47; H, 5.83; N, 8.86.

EXAMPLE IV In a manner analogous to example I, 3-(3,4-dichlorophenyl)-2-naphthoic acid is reacted with ethylenediamine to obtain 1 lb( 3,4-dich1orobenzoyl) 1 ,2,3,1 1 b-tetrahydro-5H-benz[ f imidazo[2,l-alisoindol-S-one, m.p. 2l57 C. (Rx EtOH).

Anal. Calcd for C H N- Cl 0: C, 65.05; H, 3.82; N, 7.58;

CI, 19.21. Found: C, 65.31; H, 3.66; N, 7.54; CL,18.89.

EXAMPLE V In a manner analogous to example I, 3-benzoyl-2-naphthoic acid is reacted with 1,2-diamino-2'methylpropane to obtain 2,2-dimethyl-l,2,3,l lb-tetrahydro-l 1b -phenyl-5H-benz[f]- imidazo[2,l-alisoindol-S-one, m.p. 203-5 C. (Rx EtOH). Anal. Calcd for C H N O: C, 80.45; H, 6.14; N, 8.53. Found: C, 80.45; H, 6.21; N,8.56.

EXAMPLE VI A solution of 30 g. of 1 lb-(p-chloropheny1)-1,2,31 1btetrahydro-SH-benz[f]imidazo[2,l-a]isoindol-5-one, 23 g. of p-toluensulfonyl chloride and ml. of pyridine is refluxed for 17 hours. The solution is evaporated to dryness in vacuo. The residue is slurried with ethanol and the solid is separated by filtration. On recrystallization from ethanol there is obtained 1 lb-(p-ch1orophenyl)-1,2,3,1 lb-tetrahydrol p-tolylsulfonyl)-5H- benz[f]imidazo[2,l-a]isoindol-5-one, m.p. 176-9 C.

Anal. Calcd for c u clmso C, 66.31; H, 4.33; N, 5.73.

Found: C, 66.28; H, 4.41; N, 5.84.

EXAMPLE VII In a manner analogous to example VI, l,2,3,llbtetrahydro-l 1b-phenyl-5H-benz[f]imidazo[2, l -a]isoindol-5- one is reacted with p-toluenesulfonyl chloride to obtain EXAMPLE VIII In a manner analogous to example VI, 11b-(3,4- dichlorophenyl) l ,2,31 1b-tetrahydro-5H-benz[f]imidazo[2,l -a]isoindol-5-one is reacted with p-toluenesulfonyl chloride to obtain 1 lb (3,4-dich1orophenyl)-l,2,3,l lb-tetrahydro-l-(p- EXAMPLE 1X In a manner analogous to example V1, 1,2,3,l lbtetrahydro-2methyl-l lb-phenyl-S H-benz[f]imidazo[ 2, l -a] isoindol-5-one is reacted with p-toluenesulfonyl chloride to obtain 1,2,3,1 lb-tetrahydro2-methyl-l lb-phenyll -tolylsu1- fonyl)-5H-benz[f]imidazo[2,1-a]isoindol-5-one, m.p. 2l5-7 C. (Rx EtOH).

Anal. Calcd for C H N SO C, 71.77; H, 5.17; N, 5.98.

Found: C, 71.80; H, 4.94; N, 6.08.

Example X benz[f]isoindol-l-one (20 g.) from above 13 g. of p-' toluenesulfonyl chloride and 200 ml. of pyridine are refluxed for 8 hours, the solution is evaporated to dryness. The residue is slurried with water and filtered. Recrystallization from ethanol affords 2,2-dimethyl-1,2,3 ,1 lb-tetrahydro-l lb-phenyl l-(p-tolysulfonyl)-5H-benz[f]imidazo[-a]isoindo1-5-one m.p. 2402 C.

Anal. Calcd for C H N SO C, 72.17; H, 5.43; N, 5.80.

Found: C, 72.18; H, 5.24; N, 5.83.

EXAMPLE Xl A solution of 25 g. of 1lb-(p-chlorophenyl)-l,2,3,1lbtetrahydrol p-to1ylsu1fonyl)-5 H-benz[f]imidazo[ 2, 1 -a] isoindol-S-one and 100 ml. of 95 percent sulfuric acid is allowed to stand at room temperature for 45 minutes. The mixture is quenched with several volumes of ice water then neutralized with concentrated sodium hydroxide solution. The solid is separated and washed with water. On recrystallization from dimethylacetamide there is obtained S-(p-chlorophenyl)-2,3-dihydro-SH-benz[f]imidazo-[2,l-a]isoindol-5-ol, m.p. 224-6 C.

Anal. Calcd for C ,,H,,,N C10: C, 71.74; H, 4.51; N, 8.37;

C], 10.59. Found: C, 71.91; H, 4.88; N, 8.60; Cl, 10.60.

EXAMPLE X11 A solution of 69 g. of l,2,3,11b-tetrahydro-1lb-phenyl-l- (p-tolylsulfonyl)-5H-benz[f] imidazo 2, l -a]isoindol-5-one and 200 ml. of 90 percent sulfuric acid is allowed to stand at room temperature for 45 minutes. The mixture is quenched with several volumes of ice water. The diluted solution is washed with ethylacetate. The aqueous portion is made basic with concentrated sodium hydroxide solution. The solid is separated and washed with water. On recrystallization from dimethylacetamide there is obtained 2,3-dihydro-5-phenyl-5 H-benz[f]imidazo[2,l-alisoindol-5ol, m.p. 2025 C.

Anal. Calcd for C,,,H ,N,0: C, 79.98; H, 5.37; N, 9.32.

Found: C, 79.69; H, 5.12; N, 9.37.

The hydrochloride is prepared by treating its base with hydrogenchloride m.p. 20921 1 C.

Anal. Calcd for C H N Cl0: C, 71.32; H, 5.08; N, 8.32;

CI, 10.53. Found: C, 71.1 1; H, 5.26; N, 8.40; Cl, 10.78.

EXAMPLE Xlll A solution of 23.5 g. of l,2,3,1lb-tetrahydro-Z-methyl-l 1bphenyll p-tolylsulfonyl )-5 H-benz[f]imidazo[ 2, l -a isoindol- 5-one and 75 ml. of 90 percent sulfuric acid is allowed to stand at room temperature for 45 minutes. The mixture is diluted with ice water and extracted with ethyl acetate. The aqueous portion is neutralized with concentrated sodium hydroxide solution and extracted with ethylacetate. The organic solution is evaporated to dryness. The residue is recrystallized from ethanol to obtain 2,3-dihydro-2 (or 3)methyl-5-phenyl-5H- benz[f]imidazo[2,1-a]isoindol-5-ol, m.p. 196-8 C.

Anal. Calcd for C ,H, N 0: C, 80.23; H, 5.77; N, 8.91.

Found: C, 80.52; H, 5.68; N, 8.89.

EXAMPLE IV A solution of 10 g. of 1lb-(3,4-dichlorophenyl)-1,2,3,1 1btetrahydro- 1 p-tolylsulfonyl )-5H-benz[f]imidazo[ 2, l a]isoindol-5-one and ml. of 90 percent sulfuric acid is allowed to stand at room temperature for one-half hour. The mixture is diluted with ice water and neutralized with concentrated sodium hydroxide solution. The solid is separated by filtration. On recrystallization from dilute dimethylacetamide there is obtained 5-(3,4-dichlorophenyl)-2,3-dihydro-5H- benz[f]-imidazo[2,l-a]isoindol-5-o1, m.p. 215-7 C.

Anal. Calcd for C H N OCl C, 65.05; H, 3.82; N, 7.59.

Found: C, 65.31; H, 3.99; N, 7.71.

EXAMPLE XV A solution of 20 g. of 2,2- dimethyl-l,2,3,l lb-tetrahydro- 1 lb-phenyll -(p-tolylsulfonyl )-5H-benz[f]imidazo[2, 1 -a] isoindol-S-one and 50 ml. of 90 percent sulfuric acid is allowed to stand at room temperature for 45 minutes. The mix- "ture is diluted with ice water and extracted with ethylacetate.

T aqueous portion is neutralized with concentrated sodium hydroxide solution. The solid is separated and washed with water. On recrystallization from aqueous ethanol there is obtained 2,3-dihydro-2,2( or 3,3 )diemthyl-S phenyl-SH- benz[f]imidazo[2,l-alisoindol-S-ol, m.p.197-9 C.

Anal. Calcd for CggHgoNgOi C, 80.46; H, 6.14; N, 8.53. Found: C, 80.46; H, 6.14; N, 8.71.

EXAMPLE XVl 0 R1 R4 R 1 R4 RsX wherein R., R R R R and X are as follows:

R1 R: R: R4 R5 X p-Iodophenyl Methy p-Tolylsulfonyl Chloro. 3,4-dlmethylphenyL. ......do.. Methylsulfonyl... Iodo.

p-Methoxyphenyl Hydrogen Ethylsultonyl Chloro. Hydrogen. 4-trlfluoromethylphenyL. Ethyl p-Methoxyphenylsulfonyl. Do. 9-methyl-. 2,6-dlbrom0pheny1- Hydrogen p-ChlorophenylsulfonyL. Bromo. Hydrogem. 3,4-dtmethoxyphenyl-.. Methyl 3,4-dlchlor0phenylsulfonyl. Chloro. 9-rnethoxy 2-thlonyl n-Butyl 3,6-dlmethylpheny1sultonyl. Do. Hydr0gen. p-Propoxyphenyl Methyl Propylsullonyl D0. 9 fluoro--- 2-pyr yl n-Butyl p-Tolylsulfonyl. Do. Hydrogen. 2,5-dlpropoxyphenyl. Hydrogen Phenylsullonyl Do. 8-ethyl 2-furyl do p-Ethylphenylsulfonyl. Do. 9-propylamlno- 3.4-dlethylpheny1 Methyl p-Tolylsullonyl Do. ethyl 'Ietrahydro-iZ-naphthyl. Hydrogen 3,5-dlbromophenylsullonyL- Do. Hydrogen. o-Chlorophenyl Methyl o-Chlorophenylsulfonyl Do. Q-ethyL... Phenyl. do p-Tolylsu fonyl Do. Hydrogen. 2,5-dlbuty1phenyl Hydrogen o Do. Do Phenyl Ethyl .d0 Do. 8-ethoxy-. p-Chlorophenyl l-Propyl... 4-ethoxyphenylsultony Do. Hydrogenm-Chlorophenyl Hydrogem. 4-propylphenyl. Do. S-n-propyl. 4-fluoropheny1 Ethyl p-Tolylsulfonyl. Do. S-amlno. 3,4-dlchlorophenyL. do Do. 8-butyl 4-ethoxyphenyl do Do. S-bromo- 4-bromophenyl... do Do. Hydrogen. 4-chlorophenyl.-. 2,2-dlethyl do Do. 8-chl0l'0. Phenyl. 2,2-dl-n-propyl ..do.. Bromo.

EXAMPLE XVI] B-n-butyl hydrogen 4-ethoxyphcnyl ethyl 8-bromo 9-bromo 4-bromophenyl n-propyl By procedures analogous to those employed in example X, hydrozen y g r ph nyl 2.2-dielhyl the following intermediates are prepared: P l i-f lm g y We claim: 0 l. A compound selected from the group consisting of: R1 R4 N A A B4 N NH I R2 R3 R4 ANA 2 wherein R is selected from the group consisting of hydrogen, halogen, amino, (lower)alkylamino, (lower)alkyl and OH 40 R (lower)alkoxy; R is hydrogen when R and R, are dissimilar A W and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, (lower)alkyl and (lower)alkoxy; R is selected from the group consisting of and (H) are the same as heremabove phenyl monohalophenyl, dihalophenyl, mono(lower)ale me kylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, fury] and tetrahydro-Z-naphthyl; R is selected from the group consisting of hydrogen, (lower)alkyl and gem "Ydmlen di(lower)alkyl; and the pharmaceutically acceptable salts 9-mcthoxy hydrogen 3,4 dimelhyl henyl methyl er 8-chloro 9chloro p-methoxyphenyl hydrogen 8-methylamino hydrogen d-trifluoromethyl henyl ethyl A compound defined m l whlch IDS 5 (p' 8-melhyl 9-rnethyl 2,5dibromophenyl hydrogen p y r y r 7-elhoxy hydrogen 3.4-dimethoxylphenyl methyl dQl-5- :SFL ZT h I 'EF 3. A compound as defined in claim 1 which is: 2,3-dihydro- -|o o y rogen p-propoxyp eny m y new (Munro zwridy, 5-phenyl-5H-benz[f]imidazo[ 2, l -a ]isomdo l-5-ol. hydrogen hydrogen 2.5-dipropoxyphenyl hydrogen 4. A compound as defined in claim 1 which is: 2,3-dlhydro- 8flhyl y s y hydrogen 2(or 3)-methyl-5-phenyl-5H-benz[f]imidazo[2,l-a]-isoindol- 9-pr0pylamin0 hydrogen 3.4-diethylphenyl methyl 8-clhyl lO-cthyl tctrahydro-Zmaphthyl hydrogen hydrogen hydrogen o-chlorophenyl methyl 5. A compound as defined in claim] which is: 5-(3,4- Q-cthyl hydrogen phenyl methyl dichlorophenyl)-2,3-dihydro-5 H-benz[f]imidazo[2, l-a]- hydrogen hydrogen 2,5-dibutyl henyl hydrogen i i d l s l hydrogen hydrogen phenyl ethyl xflhmy hydrogen whlomphcnyl prowl 6. A compound as defined in claim 1 which IS: 2 3-dihydrohydrogen hydrogen mchlorophenyl hydrogen 2,2(0r 3,3)-d|methyl-5-phenyl-5H-benz[f]|m|dazo-[2.1- R-n-propyl 9-nropyl 4-fluorophenyl ethyl alisoindoI-S-ol, Bomino hydrogen 3.4-dichlorophcnyl methyl It l 

2. A compound as defined in claim 1 which is: 5-(p-chlorophenyl)-2,3-dihydro-5H-benz(f)imidazo(2,1-a)isoindol-5-ol.
 3. A compound as defined in claim 1 which is: 2,3-dihydro-5-phenyl-5H-benz(f)imidazo(2,1-a)isoindol-5-ol.
 4. A compound as defined in claim 1 which is: 2,3-dihydro-2(or 3)-methyl-5-phenyl-5H-benz(f)imidazo(2,1-a) -isoindol-5-ol.
 5. A compound as defined in claim 1 which is: 5-(3,4-dichlorophenyl)-2,3-dihydro-5H-benz(f)imidazo(2,1-a)-isoindol-5-ol.
 6. A compound as defined in claim 1 which is: 2,3-dihydro-2,2(or 3,3)-dimethyl-5-phenyl-5H-benz(f)imidazo-(2,1-a)isoindol-5-ol. 